GPCR accessory proteins ͉ receptor signalling ͉ receptor trafficking T he melanocortin receptor (MCR) family is involved in a diverse range of physiologic and disease processes (1). MC1R is important in pigmentation, MC2R in steroidogenesis, and MC5R has an exocrine function especially in sebaceous gland secretion. MC3R and MC4R are both highly expressed in the brain and play key roles in energy homeostasis. Mutations in MC4R are the most common cause of monogenic obesity. More recently, fat mass, weight, risk of obesity, and insulin resistance were associated with common variants near the MC4R locus (2, 3). Both MC4R knockout mice and humans with MC4R mutations display early-onset obesity associated with hyperphagia (4, 5). MC3R knockout mice, however, develop a milder phenotype with later-onset obesity (6, 7).We previously identified MRAP (melanocortin-2-receptor accessory protein), a small transmembrane protein, as an MC2R accessory protein, enabling the functional expression of MC2R in transfected cells. The identification of MRAP provides a molecular explanation for the difficulties encountered in the expression of the MC2R in nonadrenal cell lines (8). Furthermore, mutations in MRAP result in the autosomal recessive disorder familial glucocorticoid deficiency type 2 (9).Here we report the identification and characterization of a unique MRAP homologue encoded by C6orf117 on human chromosome 6q14.3, which we have named MRAP2. We show that both MRAP and MRAP2 can modulate the signaling of all 5 MCRs. MRAP2 is primarily expressed in human brain and adrenal gland. In the brain, MRAP2 expression is seen in the hypothalamus (10), a site that also expresses a high level of MC3R and MC4R (6,11). MRAP expression in the hypothalamus has also been demonstrated by in situ hybridization (12). These findings suggest that MRAP and MRAP2 may regulate MC3R and MC4R function in the central nervous system. Results MRAP2:A Unique Homologue of MRAP. The human MRAP2 gene consists of 4 exons, and its protein product comprises 205 aa residues, with a predicted molecular mass of 23.5 kDa (Fig. 1A). MRAP2 is homologous to MRAP, with 39% amino acid identity to MRAP in the N-terminal and transmembrane domains (Fig. 1B). The protein is highly conserved through vertebrates (supporting information Fig. S1) and like MRAP has no predicted signal sequence.
ContextFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder as a result of mutation in genes encoding either the ACTH receptor [melanocortin 2 receptor (MC2R)] or its accessory protein [melanocortin 2 receptor accessory protein (MRAP)[. The disorder is known as FGD type 1 and 2, respectively.ObjectiveThe aim of the study was to compare the phenotype/genotype relationships between FGD 1 and 2.Design and patientsForty patients with missense MC2R mutations and 22 patients with MRAP mutations were included. Forty-four of these patients had been referred for genetic screening and 18 were patients published by other authors.ResultsThe median age at presentation for FGD type 1 was variable at 2·0 years; range 0·02–16 years, and this was associated with unusually tall stature, mean height SDS + 1·75 ± 1·53 (mean ± SD). In contrast, FGD type 2 presented at a much earlier median age (0·08 years; range at birth to 1·6 years) (P < 0·01) and patients were of normal height SDS + 0·12 ± 1·35 (P < 0·001). No differences in baseline cortisol or ACTH levels were seen between FGD types 1 and 2.ConclusionFGD type 2 appears to present earlier. This may reflect the functional significance of the underlying mutations in that all MRAP mutations are nonsense or splice site mutations that result in abolition of a functional protein, whereas most of the MC2R mutations are missense mutations and give rise to proteins with some residual function. Tall stature is associated with mutations in MC2R but not in MRAP. There were no other significant clinical distinctions between the two.
Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
Bioluminescence resonance energy transfer analysis is used to study the interaction between melanocortin 2 receptor (MC2R) accessory protein and the MC2R and provides evidence for protein kinase A-dependent conformational changes in the receptor complex following receptor activation.
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